SPHINGOLIPID MEDIATORS AND INTESTINAL TUMORIGENESIS

项目总结（见说明）： 鞘脂介质参与调节细胞生长、凋亡和分化的复杂细胞信号传导途径。膳食鞘磷脂在肠道中被强烈代谢成极性代谢物，如鞘氨醇和鞘氨醇1-磷酸（S1 P）。我们的实验室确定了第一个G蛋白偶联受体SIP和其受体依赖性的行动。梅里尔及其同事 已经表明，膳食鞘磷脂在肠肿瘤发生的致癌物诱导和肿瘤抑制基因缺失（ApcMin/+）模型中具有化学预防作用。此外，增加鞘脂-rlch饮食（如大豆）的摄入量（其提高细胞内鞘氨醇水平）与肠癌发病率降低相关。这些数据表明，鞘脂介质是肠道肿瘤发生的有效调节剂。 这一建议是基于这样的假设，即鞘氨醇激酶是一种关键的调节酶，通过抑制细胞内水平的肿瘤抑制脂质鞘氨醇和增强促肿瘤发生脂质介体SIP来促进肠道肿瘤发生。我们建议在小鼠肠癌模型中进一步确定分子机制并测试生物学意义。因此，具体目标是： 1.进一步明确鞘氨醇激酶在肠道肿瘤发生中的作用。 2.为了确定鞘氨醇的细胞内信号传导所涉及的分子机制， 3.我们将测试的假设，增加细胞内鞘氨醇和减少自分泌信号的81 P所带来的基因缺失Sphk酶是负责肿瘤抑制作用。饮食鞘磷脂将用于进一步增加Sphk敲除小鼠中的鞘氨醇水平，并且我们将测试这种饮食操作是否进一步影响ApcMin/-t-模型中的肠肿瘤发生。 由于肠道中的鞘脂水平可以通过饮食方式改变，这项研究有望提供一种新的癌症化学预防方法。

PROJECT SUMMARY (See instructions): Sphingolipid mediators, are involved in complex cell signaling pathways that regulate cell growth, apoptosis and differentiation. Dietary sphingomyelin is avidly metabolized in the intestinal tract into polar metabolites such as sphingosine and sphingosine 1-phosphate (S1P). Our laboratory defined the first G protein-coupled receptor for SIP and characterized its receptor-dependent actions. Merrill and colleagues have shown that dietary sphingomyelin is chemopreventive in carcinogen-induced and tumor-suppressor gene deleted (ApcMin/+) models of intestinal tumorigenesis. In addition, increased intake of sphingolipid-rlch diets (such as soy), which raises intracellular sphingosine levels is associated with reduced Incidence of intestinal cancer. These data suggest that sphingolipid mediators are potent modulators of intestinal tumorigenesis. This proposal is based on the hypothesis that sphingosine kinase is a key regulatory enzyme that facilitates intestinal tumorigenesis by suppressing intracellular levels of tumor suppressor lipid sphingosine and enhancing pro-tumorigenic lipid mediator SIP. We propose to further define molecular mechanisms and test the biological significance in mouse models of intestinal cancer. Thus, the specific aims are: 1. To further define the role of sphingosine kinase enzymes in intestinal tumorigenesis. 2. To define the molecular mechanisms involved in the intracellular signaling of sphingosine, 3. We will test the hypothesis that increased intracellular sphingosine and reduced autocrine signaling of 81P brought about by gene deletion of Sphk enzymes is responsible for tumor suppressive action. Dietary sphingomyelin will be used to further Increase sphingosine levels in Sphk knockout mice and we will test whether this dietary manipulation further influences intestinal tumorigenesis in the ApcMin/-t- model. Since sphingolipid levels in the intestine can be altered by dietary means, this research promises to provide a novel means of cancer chemoprevention.